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Significance

Bacterial secondary metabolites are of great relevance to human society and the environment. To this day, investigations of secreted metabolites focus on single compounds, compound classes, or compounds with specific bioactivities. Comparing the supernatants of Streptomyces chartreusis cultivated in different media, using liquid chromatography–coupled tandem MS, we detected a great diversity of highly regulated compounds surpassing genome-based expectations. Guided by molecular networking, a new polyether ionophore was identified and subsequently purified and characterized. The approach presented here provides a basis for structure analysis for molecules produced in amounts too low for standard methods of structure elucidation. Simultaneously, it facilitates the differential analysis of secreted metabolomes, providing insights into the chemical profiles under different cultivation conditions.

Abstract

Actinomycetes are known for producing diverse secondary metabolites. Combining genomics with untargeted data-dependent tandem MS and molecular networking, we characterized the secreted metabolome of the tunicamycin producer Streptomyces chartreusis NRRL 3882. The genome harbors 128 predicted biosynthetic gene clusters. We detected >1,000 distinct secreted metabolites in culture supernatants, only 22 of which were identified based on standards and public spectral libraries. S. chartreusis adapts the secreted metabolome to cultivation conditions. A number of metabolites are produced iron dependently, among them 17 desferrioxamine siderophores aiding in iron acquisition. Eight previously unknown members of this long-known compound class are described. A single desferrioxamine synthesis gene cluster was detected in the genome, yet different sets of desferrioxamines are produced in different media. Additionally, a polyether ionophore, differentially produced by the calcimycin biosynthesis cluster, was discovered. This illustrates that metabolite output of a single biosynthetic machine can be exquisitely regulated not only with regard to product quantity but also with regard to product range. Compared with chemically defined medium, in complex medium, total metabolite abundance was higher, structural diversity greater, and the average molecular weight almost doubled. Tunicamycins, for example, were only produced in complex medium. Extrapolating from this study, we anticipate that the larger part of bacterial chemistry, including chemical structures, ecological functions, and pharmacological potential, is yet to be uncovered.

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